We have identified the biochemical abnormality in a mutant strain of BALB/C mice which bear a certain resemblance to Niemann-Pick disease Type C as a specific impairment of esterification of exogenous cholesterol. This metabolic lesion causes organomegaly central nervous system damage and early death in this mouse analogue. Concomitant with this alteration, there is decreased activity of sphingomyelinase and glucocerebrosidase in the organs of affected animals. Activities of certain other lysosomal enzymes are increased similar to the situation often observed in humans with a lysosomal enzyme deficiency. The biochemical defect has also been demonstrated in cultured skin fibroblasts derived from affected mice and the molecular basis of this biochemical derangement is under investigation. This model should be useful to elucidate the effects of cholesterol on the activity of sphingolipid hydrolases and for developing therapeutic strategies to treat heritable metabolic disorders.